Evidence for a preferential V_β usage by the T cells which adoptively transfer diabetes in NOD mice

Abstract

Non-obese diabetic (NOD) mice become spontaneously diabetic as a result of a genetically programmed autoimmune process mediated by autoreactive T lymphocytes and directed against beta cell antigen(s). Studies dealing with T cell receptor (TcR) variable (V) gene usage by such autoreactive T lymphocytes have given contrasted results. Various reasons may explain these discrepancies: the multiplicity of antigenic epitopes putatively recognized by T cells, the ambiguity between specifically committed T cells and passenger lymphocytes homing randomly to the pancreas, the necessarily limited size of the T cell clone panels which have been analyzed for TcR rearrangements and, last but not least, the flexibility of T cell repertoires. To circumvent some of these difficulties, we have decided to concentrate upon the T cell population present in diseased animals and capable of transferring diabetes into young naive NOD recipients. This population, composed of CD4+ and CD8+ T cells, is presumably committed against the relevant beta cell antigens and is the most likely to reveal a bias in V gene usage if such a bias does indeed exist. To find out whether certain V beta genes are more frequently used than others by such pathogenic T cells, T lymphocytes from diabetic donors have been depleted in vitro of defined V beta subsets before being reinoculated into permissive recipients. Out of four V beta families probed under such conditions, three (V beta 8, V beta 5 and V beta 11) are neutral. Their absence neither increases nor reduces the final incidence of successful transfers, indicating that these gene segments are not preferentially used. In contrast, the depletion of V beta 6-positive T cells results in a severe reduction of transfers, suggesting that V beta 6 gene is used with a relatively high frequency by diabetogenic CD4+ and/or CD8+ T cells. To define more precisely which subset uses V beta 6 gene preferentially, we have performed mixing experiments with deleted and intact subsets. The results, based on disease transfer and insulitis severity, indicate that the V beta 6 bias affects predominantly the CD4+ subset. Thus, at variance with several studies concluding that V gene usage in NOD mice is heterogeneous, our present data suggest that disease transferring T cells use a relatively restricted set of V beta genes.

High-Throughput Sequencing of Islet-Infiltrating Memory CD4+ T Cells Reveals a Similar Pattern of TCR Vβ Usage in Prediabetic and Diabetic NOD Mice

“…Similarly, young NOD mice rapidly developed diabetes following transfer of clones expressing TRBV1, TRBV19, TRBV13-1, or TRBV15 with or without the B:9-23-specific Vα13 chain, demonstrating that pathogenicity was conferred by the Vβ and not the Vα chain [47]. Finally, diabetogenic CD4 + T cells depleted of Vβ6 (TRBV19) have a reduced capacity to transfer disease to young NOD mice [54]. In our study, most of the CD4 + CD44 high monoclonal expansions identified in both the prediabetic and the diabetic mice expressed TRBV1, TRBV19, or TRBV13-3.…”

T Cell Receptor Gene Usage in Desmoglein-3-Specific T Lymphocytes from Patients with Pemphigus Vulgaris

“…Subsequently, preferential TCR usage has been reported in other autoimmune animal models, such as Vb8.1 and Vb8.2 in MRL-lpr/lpr lupus mice (Singer et al, 1986); Vb8.2, Vb10, and Vb12 in experimental autoimmune myocarditis (Matsumoto et al, 2000); Vb6 in experimental autoimmune myasthenia gravis (Infante et al, 1992); and Vb6, Vb8.2, or Va13 in the non-insulin dependent diabetes mouse model (Edouard et al, 1993;Yang et al, 1996;Simone et al, 1997). Despite these ¢ndings, preferential usage of TCR genes in human autoimmune diseases is still debated (Wilson et al, 1993).…”

Constitutive Impaired TCR/CD3-mediated Activation of T cells in IDDM Patients Co-exist with Normal Co-stimulation Pathways

“…The choice of these specific TCR-V mAbs was dictated either by their relative high prevalence among peripheral T cells (V 2) or because V 8 + and V 7 + cells were previously suggested to play a role in the pathogenesis of diabetes [33,34]. In fact, oligoclonal TCR-V usage by insulitis T cells remain very controversial [3,[35][36][37][38][39]. Although only some V subsets have been investigated, we found low V -mediated proliferative response in IDDM with each monoclonal antibody tested, leading to the hypothesis that a general TCR/CD3 signaling defect underlies the hyporesponsiveness of T cells in IDDM.…”